Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia

Department of Endodontics, University of Texas Health Science Center at San Antonio, TX 78229, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 02/2009; 30(2):79-84. DOI: 10.1016/
Source: PubMed


Despite the wealth of information on cannabinoid-induced peripheral antihyperalgesic and antinociceptive effects in many pain models, the molecular mechanism(s) for these actions remains unknown. Although metabotropic cannabinoid receptors have important roles in many pharmacological actions of cannabinoids, recent studies have led to the recognition of a family of at least five ionotropic cannabinoid receptors (ICRs). The known ICRs are members of the family of transient receptor potential (TRP) channels and include TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1. Cannabinoid activation of ICRs can result in desensitization of the TRPA1 and TRPV1 channel activities, inhibition of nociceptors and antihyperalgesia and antinociception in certain pain models. Thus, cannabinoids activate both metabotropic and ionotropic mechanisms to produce peripheral analgesic effects. Here, we provide an overview of the pharmacology of TRP channels as ICRs.

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Available from: Armen N Akopian, Feb 06, 2015
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    • "The majority of ICRs are expressed in nociceptive sensory neurons, which can detect and respond to noxious mechanical, thermal and chemical stimuli. Nevertheless, the cannabinoids produce a profound antihyperalgesia and the mechanism has not yet been established [115]. "
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    ABSTRACT: The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via β -arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia.
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    • "Finally, transient receptor potential vanilloid-2 (TRPV2) and melastatin-8 (TRPM8) channels are also expressed in sensory neurons and it has been suggested they play a role in pain. Interestingly, all these channels, like TRPV1, are known to be modulated by plant cannabinoids and endocannabinoids, and are thought to act as 'ionotropic cannabinoid receptors' (De Petrocellis et al., 2011; see Akopian et al., 2009 and De Petrocellis and Di Marzo, 2010, for reviews). It was hypothesized that peripheral tissue injury leads to the generation of endogenous TRPV1 ligands in the spinal cord, which then activate TRPV1 in the CNS, resulting in central sensitization contributing to mechanical allodynia. "
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    ABSTRACT: Two oxidation products of linoleic acid, 9- and 13-hydroxy-octadecadienoic acids (HODEs), have recently been suggested to act as endovanilloids, that is, endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) channels, thereby contributing to inflammatory hyperalgesia in rats. However, HODE activity at rat TRPV1 in comparison with the best established endovanilloid, anandamide, and its enantioselectivity and selectivity towards other TRP channels that are also abundant in sensory neurons have never been investigated. We studied the effect of 9(R)-HODE, 9(S)-HODE, (+/–)13-HODE, 15(S)-hydroxyanandamide and anandamide on [Ca2+]i in HEK-293 cells stably expressing the rat or human recombinant TRPV1, or rat recombinant TRPV2, TRPA1 or TRPM8, and also the effect of 9(S)-HODE in rat dorsal root ganglion (DRG) neurons by calcium imaging. Anandamide and 15(S)-hydroxyanandamide were the most potent endovanilloids at human TRPV1, whereas 9(S)-HODE was approximately threefold less efficacious and 75- and 3-fold less potent, respectively, and did not perform much better at rat TRPV1. The 9(R)-HODE and (+/–)13-HODE were almost inactive at TRPV1. Unlike anandamide and 15(S)-hydroxyanandamide, all HODEs were very weak at desensitizing TRPV1 to the action of capsaicin, but activated rat TRPV2 [only (+/–)13-HODE] and rat TRPA1, and antagonized rat TRPM8, at concentrations higher than those required to activate TRPV1. Finally, 9(S)-HODE elevated [Ca2+]i in DRG neurons almost exclusively in capsaicin-sensitive cells but only at concentrations between 25 and 100 μM. The present data suggest that HODEs are less important endovanilloids than anandamide. This article is part of a themed section on Cannabinoids. To view the other articles in this section visit
    British Journal of Pharmacology 08/2012; 167(8). DOI:10.1111/j.1476-5381.2012.02122.x · 4.84 Impact Factor
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    • "Although the most well-known molecular targets for cannabinoids are the G protein-coupled receptors CB 1 (Matsuda et al., 1990) and CB 2 (Munro et al., 1993), TRP channels have attracted recent attention as additional targets (Akopian et al., 2009). TRP channels are nonselective ion channels that directly gate the influx of cations into the cell in response to diverse stimuli (Bandell et al., 2007). "
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